Synergistic therapies for intervertebral disc degeneration

ABSTRACT

A method for treating an intervertebral disc of a subject is provided, the method including delivering a growth factor to a nucleus pulposus of the intervertebral disc. At least one intra-pulposus exposed electrode surface is implanted in the nucleus pulposus. At least one extra-pulposus exposed electrode surface is implanted in a body of the subject outside the nucleus pulposus. The growth factor is supported by activating control circuitry to drive the intra-pulposus and the extra-pulposus exposed electrode surfaces to electroosmotically drive nutrient-containing fluid into the nucleus pulposus. Other embodiments are also described.

FIELD OF THE APPLICATION

The present invention relates generally to treatment of intervertebraldisc degeneration.

BACKGROUND OF THE APPLICATION

The intervertebral discs form cartilaginous joints between the endplatesof vertebrae to provide shock absorption. The discs include two mainregions: the nucleus pulposus, which is an inner, soft and highlyhydrated structure, and the annulus fibrosus, which is a strongstructure including lamellae (concentric sheets of collagen fibers),which surrounds the nucleus. The three major constituents of the discsare water, fibrillar collagens, and aggrecan. The proportion of thesecomponents varies across the disc, with the nucleus having a higherconcentration of aggrecan and water and a lower collagen content thanother regions of the disc. The loss of water content, particularly inthe nucleus pulposus, is associated with disc degeneration, and with adecrease in disc height and abnormal loading of other spinal structures.

U.S. Pat. No. 8,577,469 to Gross, which is assigned to the assignee ofthe present application and is incorporated herein by reference,describes apparatus for treating an intervertebral disc of a subject.The apparatus includes a first electrode, configured to be inserted intoa nucleus pulposus of the disc, and a second electrode, configured to beplaced outside of the nucleus pulposus, in a vicinity of the nucleuspulposus. A control unit is configured to drive a current between thefirst and second electrodes, and to configure the current toelectroosmotically drive fluid between inside and outside the nucleuspulposus. Other embodiments are also described

US Patent Application Publication 2005/0277996 to Podhajsky describes amethod for reducing intervertebral pressure, including providing anelectrode, having proximal and distal ends, and a generator, which isoperatively connected to the proximal end of the electrode, and isconfigured to supply radiofrequency current thereto. The method alsoincludes inserting at least a portion of the distal end of the electrodeinto the nucleus pulposus of an intervertebral disc and activating thegenerator to heat the nucleus pulposus. The electrode may be insertedinto the intervertebral disc through its first lateral side and/or itssecond lateral side, and may be substantially parallel to the major orminor axis of the nucleus pulposus.

SUMMARY OF THE APPLICATION

Some embodiments of the present invention provide methods for combinedtherapy for the treatment of an intervertebral disc of a subject. Thecombination of cell therapy and/or growth factors with the restorationof the electrochemical osmotic properties of the disc provides thenutritional supply to regenerate the disc tissue and restore pumping-outof cytokines and pain markers. Some of the methods comprise deliveringcells or a growth factor to a nucleus pulposus of the intervertebraldisc, or administering gene therapy to nucleus pulposus cells. At leastone intra-pulposus exposed electrode surface is implanted in the nucleuspulposus, and at least one extra-pulposus exposed electrode surface isimplanted in a body of the subject outside the nucleus pulposus. Thecells, growth factor, or gene therapy, as the case may be, are supportedby activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivenutrient-containing fluid into the nucleus pulposus. For someapplications, the nutrient-containing fluid includes oxygen and/orglucose.

Other methods of the present invention comprise implanting at least oneintra-pulposus exposed electrode surface in the nucleus pulposus, andthe at least one extra-pulposus exposed electrode surface in the body ofthe subject outside the nucleus pulposus. Control circuitry is activatedto drive the intra-pulposus and the extra-pulposus exposed electrodesurfaces to electroosmotically drive fluid into the nucleus pulposus.Enzyme therapy is administered to the intervertebral disc or itssurroundings so as to facilitate electroosmotically driving the fluidinto the nucleus pulposus. Alternatively or additionally, supplementalfluid is delivered (e.g., injected) to the intervertebral disc (thenucleus pulposus or the annulus fibrosus) or into tissue surrounding theintervertebral disc.

Still other methods of the present invention comprise delivering (e.g.,injecting), to the intervertebral disc (the nucleus pulposus or theannulus fibrosus) or into tissue surrounding the intervertebral disc, abiomaterial configured to treat degeneration of the intervertebral disc.Control circuitry is activated to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivefluid into the nucleus pulposus.

There is therefore provided, in accordance with an Inventive Concept 1of the present invention, a method for treating an intervertebral discof a subject, the method including:

delivering cells to a nucleus pulposus of the intervertebral disc;

implanting at least one intra-pulposus exposed electrode surface in thenucleus pulposus;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; and

supporting the delivered cells by activating control circuitry to drivethe intra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive nutrient-containing fluid into the nucleuspulposus.

Inventive Concept 2. The method according to Inventive Concept 1,wherein delivering the cells to the nucleus pulposus includes injectingthe cells into the nucleus pulposus.Inventive Concept 3. The method according to Inventive Concept 1,wherein delivering the cells to the nucleus pulposus includes deliveringthe cells to the body of the subject outside the nucleus pulposus suchthat the cells migrate into the nucleus pulposus.Inventive Concept 4. The method according to Inventive Concept 3,wherein delivering the cells to the body of the subject outside thenucleus pulposus includes delivering the cells to a vertebral endplatesuch that the cells migrate into the nucleus pulposus.Inventive Concept 5. The method according to Inventive Concept 3,wherein delivering the cells to the nucleus pulposus includes deliveringthe cells to an annulus fibrosus of the intervertebral disc.Inventive Concept 6. The method according to Inventive Concept 3,wherein delivering the cells to the nucleus pulposus includes, while atleast some of the cells are outside the nucleus pulposus, activating thecontrol circuitry to drive the intra-pulposus and the extra-pulposusexposed electrode surfaces to electroosmotically drive the cells intothe nucleus pulposus.Inventive Concept 7. The method according to Inventive Concept 1,wherein supporting the delivered cells includes supporting the deliveredcells by activating the control circuitry to apply a mean voltage ofless than 1.23 V between the intra-pulposus exposed electrode surfaceand the extra-pulposus exposed electrode surface, so as not to causeelectrolysis.Inventive Concept 8. The method according to Inventive Concept 1,wherein activating the control circuitry includes activating the controlcircuitry to:

repeatedly assume an electroosmotic mode of operation in alternationwith an oxygen-generating mode of operation,

in the electroosmotic mode of operation, electroosmotically drive thenutrient-containing fluid into the nucleus pulposus, by applying a meanvoltage of less than 1.23 V between the intra-pulposus exposed electrodesurface and the extra-pulposus exposed electrode surface, and

in the oxygen-generating mode of operation, generate oxygen within thenucleus pulposus by electrolysis, by applying a mean voltage of at least1.23 V between the intra-pulposus exposed electrode surface and theextra-pulposus exposed electrode surface.

Inventive Concept 9. The method according to Inventive Concept 8,wherein activating the control circuitry includes activating the controlcircuitry to, during a period of time, assume (a) the electroosmoticmode of operation at least 10 times for an aggregate first duration and(b) the oxygen-generating mode of operation at least 10 times for anaggregate second duration that is less than 10% of the aggregate firstduration.Inventive Concept 10. The method according to Inventive Concept 9,wherein the aggregate second duration is less than 1% of the aggregatefirst duration.Inventive Concept 11. The method according to Inventive Concept 1,wherein the nutrient-containing fluid includes oxygen, and whereinsupporting the delivered cells includes supporting the delivered cellsby activating the control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe oxygen-containing fluid into the nucleus pulposus.Inventive Concept 12. The method according to Inventive Concept 1,wherein the nutrient-containing fluid includes glucose, and whereinsupporting the delivered cells includes supporting the delivered cellsby activating the control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe glucose-containing fluid into the nucleus pulposus.Inventive Concept 13. The method according to Inventive Concept 1,wherein delivering the cells to the nucleus pulposus includes deliveringstem cells to the nucleus pulposus.Inventive Concept 14. The method according to Inventive Concept 1,wherein delivering the cells to the nucleus pulposus includes deliveringdisc cells to the nucleus pulposus.Inventive Concept 15. The method according to Inventive Concept 1,wherein delivering the cells to the nucleus pulposus includes deliveringnotochordal cells to the nucleus pulposus.Inventive Concept 16. The method according to Inventive Concept 1,wherein supporting the delivered cells includes supporting the deliveredcells by activating the control circuitry to intermittently drive,during a plurality of sessions, the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe nutrient-containing fluid into the nucleus pulposus.Inventive Concept 17. The method according to Inventive Concept 16,wherein an average duration of non-activation periods between sequentialones of the sessions is at least 12 hours.Inventive Concept 18. The method according to Inventive Concept 16,wherein the plurality of sessions includes at least 10 sessions.Inventive Concept 19. The method according to Inventive Concept 16,wherein supporting the delivered cells includes supporting the deliveredcells by activating the control circuitry to intermittently drive theintra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive the nutrient-containing fluid into the nucleuspulposus during one or more of the sessions during each 24-hour period.Inventive Concept 20. The method according to Inventive Concept 19,wherein supporting the delivered cells includes supporting the deliveredcells by activating the control circuitry to intermittently drive theintra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive the nutrient-containing fluid into the nucleuspulposus during exactly one of the sessions during each 24-hour period.Inventive Concept 21. The method according to Inventive Concept 16,wherein the plurality of sessions extends over at least one week.Inventive Concept 22. The method according to Inventive Concept 1,wherein supporting the delivered cells includes supporting the deliveredcells by activating the control circuitry to apply direct currentbetween the intra-pulposus and the extra-pulposus exposed electrodesurfaces.Inventive Concept 23. The method according to Inventive Concept 1,further including delivering an enzyme to the intervertebral disc ortissue around the intervertebral disc so as to facilitateelectroosmotically driving the nutrient-containing fluid into thenucleus pulposus.

There is therefore provided, in accordance with an Inventive Concept 24of the present invention, a method for treating an intervertebral discof a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

delivering cells to the body of the subject outside the nucleuspulposus; and

while at least some of the cells are outside the nucleus pulposus,activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe cells into the nucleus pulposus.

Inventive Concept 25. The method according to Inventive Concept 24,further including supporting the delivered cells by activating thecontrol circuitry to drive the intra-pulposus and the extra-pulposusexposed electrode surfaces to electroosmotically drivenutrient-containing fluid into the nucleus pulposus.Inventive Concept 26. The method according to Inventive Concept 24,wherein delivering the cells to the body of the subject outside thenucleus pulposus includes delivering the cells to a vertebral endplate.Inventive Concept 27. The method according to Inventive Concept 24,wherein delivering the cells to the body of the subject outside thenucleus pulposus includes delivering the cells to an annulus fibrosus ofthe intervertebral disc.

There is therefore provided, in accordance with an Inventive Concept 28of the present invention, a method for treating an intervertebral discof a subject, the method including:

administering gene therapy to nucleus pulposus cells of a nucleuspulposus of the intervertebral disc;

implanting at least one intra-pulposus exposed electrode surface in thenucleus pulposus;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; and

supporting the gene therapy by activating control circuitry to drive theintra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive nutrient-containing fluid into the nucleuspulposus.

Inventive Concept 29. The method according to Inventive Concept 28,wherein supporting the gene therapy includes supporting the gene therapyby activating the control circuitry to apply a mean voltage of less than1.23 V between the intra-pulposus exposed electrode surface and theextra-pulposus exposed electrode surface, so as not to causeelectrolysis.

There is therefore provided, in accordance with an Inventive Concept 30of the present invention, a method for treating an intervertebral discof a subject, the method including:

delivering a growth factor to a nucleus pulposus of the intervertebraldisc;

implanting at least one intra-pulposus exposed electrode surface in thenucleus pulposus;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; and

supporting the growth factor by activating control circuitry to drivethe intra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive nutrient-containing fluid into the nucleuspulposus.

Inventive Concept 31. The method according to Inventive Concept 30,wherein delivering the growth factor to the nucleus pulposus includesinjecting the growth factor into the nucleus pulposus.Inventive Concept 32. The method according to Inventive Concept 30,wherein delivering the growth factor to the nucleus pulposus includesdelivering the growth factor to the body of the subject outside thenucleus pulposus such that the growth factor moves into the nucleuspulposus.Inventive Concept 33. The method according to Inventive Concept 32,wherein delivering the growth factor to the body of the subject outsidethe nucleus pulposus includes delivering the growth factor to avertebral endplate such that the growth factor moves into the nucleuspulposus.Inventive Concept 34. The method according to Inventive Concept 32,wherein delivering the growth factor to the body of the subject outsidethe nucleus pulposus includes delivering the growth factor to an annulusfibrosus of the intervertebral disc such that the growth factor movesinto the nucleus pulposus.Inventive Concept 35. The method according to Inventive Concept 32,wherein delivering the growth factor to the nucleus pulposus includes,while at least some of the growth factor is outside the nucleuspulposus, activating the control circuitry to drive the intra-pulposusand the extra-pulposus exposed electrode surfaces to electroosmoticallydrive the growth factor into the nucleus pulposus.Inventive Concept 36. The method according to Inventive Concept 30,wherein supporting the growth factor includes supporting the growthfactor by activating the control circuitry to apply a mean voltage ofless than 1.23 V between the intra-pulposus exposed electrode surfaceand the extra-pulposus exposed electrode surface, so as not to causeelectrolysis.

There is therefore provided, in accordance with an Inventive Concept 37of the present invention, a method for treating an intervertebral discof a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

delivering a growth factor to the body of the subject outside thenucleus pulposus; and

while at least some of the growth factor is outside the nucleuspulposus, activating control circuitry to drive the intra-pulposus andthe extra-pulposus exposed electrode surfaces to electroosmoticallydrive the growth factor into the nucleus pulposus.

Inventive Concept 38. The method according to Inventive Concept 37,further including supporting the growth factor by activating controlcircuitry to drive the intra-pulposus and the extra-pulposus exposedelectrode surfaces to electroosmotically drive nutrient-containing fluidinto the nucleus pulposus.Inventive Concept 39. The method according to Inventive Concept 37,wherein delivering the growth factor to the body of the subject outsidethe nucleus pulposus includes delivering the growth factor to avertebral endplate.Inventive Concept 40. The method according to Inventive Concept 37,wherein delivering the growth factor to the body of the subject outsidethe nucleus pulposus includes delivering the growth factor to an annulusfibrosus of the intervertebral disc.

There is therefore provided, in accordance with an Inventive Concept 41of the present invention, a method for treating an intervertebral discof a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivefluid into the nucleus pulposus; and

delivering an enzyme to the intervertebral disc or tissue around theintervertebral disc so as to facilitate electroosmotically driving thefluid into the nucleus pulposus.

Inventive Concept 42. The method according to Inventive Concept 41,wherein activating the control circuitry includes activating the controlcircuitry to apply a mean voltage of less than 1.23 V between theintra-pulposus exposed electrode surface and the extra-pulposus exposedelectrode surface, so as not to cause electrolysis.

There is therefore provided, in accordance with an Inventive Concept 43of the present invention, a method for treating an intervertebral discof a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

administering an enzyme to the body of the subject outside the nucleuspulposus; and

while at least some of the enzyme outside is the nucleus pulposus,activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe enzyme into the nucleus pulposus.

There is therefore provided, in accordance with an Inventive Concept 44of the present invention, a method for treating an intervertebral discof a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivebodily fluid from the body of the subject into the nucleus pulposus; and

delivering supplemental fluid to the intervertebral disc or tissuesurrounding the intervertebral disc.

Inventive Concept 45. The method according to Inventive Concept 44,wherein delivering the supplemental fluid includes delivering salinesolution to the intervertebral disc or tissue surrounding theintervertebral disc.Inventive Concept 46. The method according to Inventive Concept 44,wherein delivering the supplemental fluid includes delivering anutrient-containing fluid to the intervertebral disc or tissuesurrounding the intervertebral disc.Inventive Concept 47. The method according to Inventive Concept 44,

wherein delivering the supplemental fluid includes intermittentlydelivering, during a plurality of delivery sessions, the supplementalfluid to the intervertebral disc or tissue surrounding theintervertebral disc, and

wherein activating the control circuitry includes activating the controlcircuitry to intermittently drive, during a plurality of drivingsessions, the intra-pulposus and the extra-pulposus exposed electrodesurfaces to electroosmotically drive the supplemental fluid into thenucleus pulposus.

Inventive Concept 48. The method according to Inventive Concept 44,wherein delivering the supplemental fluid includes delivering thesupplemental fluid from a reservoir implanted in the body of thesubject.

There is therefore provided, in accordance with an Inventive Concept 49of the present invention, a method for treating degeneration of anintervertebral disc of a subject, the method including:

delivering, to the intervertebral disc or tissue around theintervertebral disc, a biomaterial configured to treat the degeneration;

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; and

activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivefluid into the nucleus pulposus.

Inventive Concept 50. The method according to Inventive Concept 49,wherein the biomaterial includes a gel.Inventive Concept 51. The method according to Inventive Concept 49,wherein the biomaterial includes a structural filler.Inventive Concept 52. The method according to Inventive Concept 49,wherein the biomaterial includes a matrix.Inventive Concept 53. The method according to Inventive Concept 49,wherein the biomaterial includes a polymer.Inventive Concept 54. The method according to Inventive Concept 49,wherein the biomaterial includes hyaluronic acid.Inventive Concept 55. The method according to Inventive Concept 49,wherein delivering the biomaterial to the nucleus pulposus includesdelivering the biomaterial to the tissue around the intervertebral discsuch that the biomaterial moves into the nucleus pulposus.Inventive Concept 56. The method according to Inventive Concept 55,wherein delivering the biomaterial to the tissue around theintervertebral disc includes delivering the biomaterial to a vertebralendplate such that the biomaterial moves into the nucleus pulposus.Inventive Concept 57. The method according to Inventive Concept 55,wherein delivering the biomaterial to the tissue around theintervertebral disc includes delivering the biomaterial to an annulusfibrosus of the intervertebral disc such that the biomaterial moves intothe nucleus pulposus.Inventive Concept 58. The method according to Inventive Concept 55,wherein delivering the biomaterial to the nucleus pulposus includes,while at least some of the biomaterial is outside the nucleus pulposus,activating the control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe biomaterial into the nucleus pulposus.

There is therefore provided, in accordance with an Inventive Concept 59of the present invention, a method for treating degeneration of anintervertebral disc of a subject, the method including:

implanting at least one intra-pulposus exposed electrode surface in anucleus pulposus of the intervertebral disc;

implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus;

delivering, to the body of the subject outside the nucleus pulposus, abiomaterial configured to treat the degeneration;

while at least some of the biomaterial is outside the nucleus pulposus,activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivethe biomaterial into the nucleus pulposus.

There is therefore provided, in accordance with an Inventive Concept 60of the present invention, a method for implanting an electrode, themethod including:

inserting a needle into tissue of a body of a subject such that (a) adistal longitudinal portion of the needle, including a distal end of theneedle, is positioned within a nucleus pulposus of an intervertebraldisc of the subject, and (b) a proximal portion of the needle, includinga proximal end opening of the needle, remain outside the subject's body;

distally advancing the electrode into the needle while a stylet isdisposed within a longitudinal channel defined by a coiled wire of theelectrode;

distally advancing the electrode and the stylet together through theneedle until a distal non-electrically-insulated longitudinal segment ofthe coiled wire of the electrode is positioned within the nucleuspulposus, and the stylet, the needle, and the coiled wire remainpartially outside the subject's body, with the stylet and the coiledwire extending proximally out of a proximal end of the needle;

thereafter, while holding the stylet axially stationary with respect tothe nucleus pulposus, proximally withdrawing the needle from thesubject's body, leaving the distal non-electrically-insulatedlongitudinal segment of the coiled wire within the nucleus pulposus,with a distal end of the stylet within the longitudinal channel of thecoiled wire, including within the distal non-electrically-insulatedlongitudinal segment; and

proximally withdrawing the stylet from the subject's body and from thelongitudinal channel of the coiled wire, while leaving the distalnon-electrically-insulated longitudinal segment of the coiled wirewithin the nucleus pulposus.

Inventive Concept 61. The method according to Inventive Concept 60,wherein distally advancing the needle through the tissue into thenucleus pulposus includes distally advancing the needle through thetissue into the nucleus pulposus while the distalnon-electrically-insulated longitudinal segment of the coiled wire isconstrained only by the needle and the stylet.Inventive Concept 62. The method according to Inventive Concept 60,

wherein the electrode further includes a tubular insulator in which thecoiled wire is partially disposed, with the distalnon-electrically-insulated longitudinal segment of the coiled wireextending distally out of a distal end of the tubular insulator, and

wherein proximally withdrawing the needle includes proximallywithdrawing the needle while leaving (a) the distalnon-electrically-insulated longitudinal segment of the coiled wirewithin the nucleus pulposus, and (b) the tubular insulator at leastpartially within the subject's body, at least partially outside thenucleus pulposus.

Inventive Concept 63. The method according to Inventive Concept 62,wherein proximally withdrawing the needle includes proximallywithdrawing the needle while leaving the tubular insulator at leastpartially within an annulus fibrosus of the intervertebral disc.Inventive Concept 64. The method according to Inventive Concept 60,further including driving the electrode to apply a current to thenucleus pulposus.Inventive Concept 65. The method according to Inventive Concept 60,wherein the stylet is coated with a friction-reducing coating.Inventive Concept 66. The method according to Inventive Concept 60,

wherein the needle includes a plurality of radiopaque markers, and

wherein distally advancing the needle through the tissue into thenucleus pulposus includes observing the radiopaque markers to confirmthat the distal longitudinal portion of the needle is disposed in thenucleus pulposus.

Inventive Concept 67. The method according to Inventive Concept 66,wherein the plurality of radiopaque markers are arranged as a ruleralong the needle.Inventive Concept 68. The method according to Inventive Concept 60,wherein the electrode includes a distal-most non-coiled tip, which isdisposed at a distal end of the coiled wire, and which is shaped so asto define a proximally-facing surface.Inventive Concept 69. The method according to Inventive Concept 68,wherein the distal-most non-coiled tip is shaped so as to define anatraumatic distally-facing end surface.Inventive Concept 70. The method according to Inventive Concept 69,wherein the atraumatic distally-facing end surface is spherical.Inventive Concept 71. The method according to Inventive Concept 68,wherein the distal-most non-coiled tip is electrically conductive and iscoupled in electrical communication with the coiled wire.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B are schematic illustrations of a method for treating anintervertebral disc of a subject, in accordance with some applicationsof the present invention;

FIG. 2 is a flowchart schematically illustrating the method of FIGS.1A-B, in accordance with some applications of the present invention;

FIG. 3 is a flowchart schematically illustrating another method fortreating an intervertebral disc, in accordance with some applications ofthe present invention;

FIG. 4 is a flowchart schematically illustrating yet another method fortreating an intervertebral disc, in accordance with some applications ofthe present invention;

FIG. 5 is a flowchart schematically illustrating still another methodfor treating an intervertebral disc, in accordance with someapplications of the present invention;

FIG. 6 is a flowchart schematically illustrating another method fortreating an intervertebral disc, in accordance with some applications ofthe present invention;

FIGS. 7A-B are flowcharts schematically illustrating yet additionalmethods for treating an intervertebral disc, in accordance with somerespective applications of the present invention;

FIG. 8 is a schematic illustration of a kit, in accordance with anapplication of the present invention;

FIGS. 9A-J are schematic illustrations of a method for implanting anelectrode in a nucleus pulposus, in accordance with an application ofthe present invention; and

FIG. 10 is a schematic illustration of a connector, in accordance withan application of the present invention.

DETAILED DESCRIPTION OF APPLICATIONS

FIGS. 1A-B are schematic illustrations of a method for treating anintervertebral disc 20 of a subject, in accordance with someapplications of the present invention.

FIG. 2 is a flowchart schematically illustrating the method of FIGS.1A-B, in accordance with some applications of the present invention.

At a cell delivery step 30 of the method, cells 32 are delivered to anucleus pulposus 34 of intervertebral disc 20, such as shown in FIG. 1A.By way of example, cells 32 are shown being injected into nucleuspulposus 34 via an annulus fibrosus 48 of disc 20. Cells 32 mayalternatively or additionally be delivered to nucleus pulposus 34 inother ways, such as into a vertebral endplate, into nucleus pulposus 34via a vertebral endplate, and/or to the body of the subject outside thenucleus pulposus (typically to tissue around intervertebral disc 20),which may be less invasive; when delivered in these other ways, cells 32migrate into nucleus pulposus 34, optionally because of theelectroosmotically driving of fluid into nucleus pulposus 34 byactivation of control circuitry 50 to drive intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42, such as describedherein. Alternatively, cells 32 may be delivered into an annulusfibrosus 48, in which case cells 32 may optionally migrate into nucleuspulposus 34 by activation of control circuitry 50 to driveintra-pulposus and extra-pulposus exposed electrode surfaces 38 and 42,such as described herein. All of the ways of delivery cells 32 mayoptionally be performed, for example, by injecting or by releasing(e.g., slow-releasing) the cells from a container, such as an implantedcontainer.

At an intra-pulposus electrode implantation step 36, at least oneintra-pulposus exposed electrode surface 38 (which is electricallyconductive) is implanted (typically chronically) in nucleus pulposus 34,such as shown in FIG. 1B. Optionally, techniques described hereinbelowwith reference to FIG. 8 and/or FIGS. 9A-J are used to implant the atleast one intra-pulposus exposed electrode surface 38.

At an extra-pulposus electrode implantation step 40, at least oneextra-pulposus exposed electrode surface 42 (which is electricallyconductive) is implanted (typically chronically) in a body 44 of thesubject outside nucleus pulposus 34, such as shown in FIG. 1B. Forexample, extra-pulposus exposed electrode surface 42 may be implanted ina vicinity of an external surface of annulus fibrosus 48 of disc 20,either in physical contact with the external surface or not in physicalcontact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

For some applications, a plurality of extra-pulposus exposed electrodesurfaces 42 (e.g., at least 3, no more than 10, and/or between 3 and 10,such as exactly 3) are implanted (typically chronically) in body 44outside nucleus pulposus 34, or are placed outside body 44.

For some applications, cells 32 include one or more of the followingtypes of cells: autologous or allogenic stem cells (e.g., mesenchymalstem cells (MSCs)), disc cells (e.g., allogeneic disc cells),notochordal cells, allogeneic chondrocytes, and/or dermal fibroblastcells. For example, the MSCs may be derived from bone marrow aspirate orfrom adipose tissue, and/or may include autologous MSCs cultured innormal or hypoxic conditions.

At a cell support step 46, delivered cells 32 are supported byactivating control circuitry 50 to drive intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive nutrient-containing fluid into nucleus pulposus34.

Small nutrients such as oxygen and glucose are supplied to the disc'scells virtually entirely by diffusion; convective transport, arisingfrom load-induced fluid movement in and out of the disc, has virtuallyno direct influence on transport of these nutrients. Consequently, thereare steep concentration gradients of oxygen, glucose, and lactic acidacross the disc; oxygen and glucose concentrations are lowest in thecenter of the nucleus where lactic acid concentrations are greatest. Theactual levels of concentration depend on the balance between diffusivetransport and cellular demand and can fall to critical levels if theendplate calcifies or nutritional demand increases.

As used in the present application, including in the claims, a“nutrient” is a substance used by cells within nucleus pulposus 34,including, for example, delivered cells 32, to survive and reproduce. Asused in the present application, including in the claims, oxygen isconsidered a nutrient, because oxygen is essential for the survival andreproduction of cells.

For some applications, the nutrient-containing fluid includes oxygen,and, at cell support step 46, delivered cells 32 are supported byactivating control circuitry 50 to drive intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive the oxygen-containing fluid into nucleuspulposus 34.

Alternatively or additionally, for some applications, thenutrient-containing fluid includes glucose, and, at cell support step46, delivered cells 32 are supported by activating control circuitry 50to drive intra-pulposus and extra-pulposus exposed electrode surfaces 38and 42 to electroosmotically drive the glucose-containing fluid intonucleus pulposus 34.

Intra-pulposus electrode implantation step 36 may be performed before,after, or simultaneously with extra-pulposus electrode implantation step40.

Intra-pulposus electrode implantation step 36 and extra-pulposuselectrode implantation step 40 may be performed before or after celldelivery step 30. Alternatively, one of intra-pulposus electrodeimplantation step 36 and extra-pulposus electrode implantation step 40may be performed before cell delivery step 30, and the otherimplantation step may be performed after cell delivery step 30. Ifintra-pulposus electrode implantation step 36 is performed before celldelivery step 30, cell delivery step 30 may optionally be performedusing connector 300, described hereinbelow with reference to FIG. 10.

Optionally, an additional cell delivery step 30 is performed after cellsupport step 46, such as months or years after cell support step 46,such as if cells 32 need to be replaced or supplemented. This additionalcell delivery step 30 may optionally be performed using connector 300,described hereinbelow with reference to FIG. 10.

For some applications, at cell support step 46, delivered cells 32 aresupported by activating control circuitry 50 to apply a mean voltage ofless than 1.23 V between intra-pulposus exposed electrode surface 38 andextra-pulposus exposed electrode surface 42, so as not to causeelectrolysis. For example, the mean voltage may be less than 1 V, suchas less than 500 mV, e.g., less than 300 mV.

For some applications, at cell support step 46, delivered cells 32 aresupported by activating control circuitry 50 to apply direct currentbetween intra-pulposus and extra-pulposus exposed electrode surfaces 38and 42. For some applications, control circuitry 50 is activated toapply the direct current during alternating “on” and “off” periods; forexample, the “on” periods may have an average duration of up to 1800seconds, and the “off” periods may have an average duration of up to 300seconds. For some applications, control circuitry 50 is activated toapply the direct current with an average amplitude of between 100 nA and5 mA, such as between 1 and 5 mA. For some applications, the controlunit is configured to apply the direct current as a series of pulses.For some applications, the control unit is configured to apply thedirect current as the series of pulses with a duty cycle of between 20%and 95%.

For some applications, control circuitry 50 is activated to apply avoltage of between 0.6-2 V, such as between 0.6 and 1.23 V, betweenintra-pulposus and extra-pulposus exposed electrode surfaces 38 and 42.

Typically, control circuitry 50 is not configured to actively balancethe applied positive and negative charges. Rather, control circuitry 50is configured to allow the passive balancing of the applied positive andnegative charges.

For some applications, control circuitry 50 is activated to driveintra-pulposus and extra-pulposus exposed electrode surfaces 38 and 42for a total duration of between 6 and 24 hours per day.

For some applications, the method further comprises delivering an enzymeto intervertebral disc 20 or tissue around intervertebral disc 20 so asto facilitate electroosmotically driving the nutrient-containing fluidinto nucleus pulposus 34.

This delivery may be performed using the techniques describedhereinbelow with reference to FIG. 5.

Reference is made to FIG. 1B. Typically, intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 and controlcircuitry 50 are elements of an intervertebral-disc-treatment system 52.Control circuitry 50 is typically electrically coupled, by one or moreelectrode leads 54, to intra-pulposus and extra-pulposus exposedelectrode surfaces 38 and 42.

Optionally, intra-pulposus extra-pulposus exposed electrode surface 38,extra-pulposus exposed electrode surface 42, and/or control circuitry 50may implement any of the techniques described in WO 2018/051338 to Grosset al., which is incorporated herein by reference.

Reference is again made to FIGS. 1A-B and 2. Typically, a healthcareworker, such as a physician, activates control circuitry 50 to providethe functions described herein. Activating the control circuitry mayinclude configuring parameters and/or functions of the control circuitry(such as using a separate programmer or external controller), oractivating the control circuitry to perform functions pre-programmed inthe control circuitry. Control circuitry 50 typically comprisesappropriate memory, processor(s), and hardware running software that isconfigured to provide the functionality of the control circuitrydescribed herein.

Reference is still made to FIGS. 1A-B and 2. For some applications,control circuitry 50 is activated to:

-   -   repeatedly assume an electroosmotic mode of operation in        alternation with an oxygen-generating mode of operation,    -   in the electroosmotic mode of operation, electroosmotically        drive the nutrient-containing fluid into nucleus pulposus 34, by        applying a mean voltage of less than 1.23 V between        intra-pulposus exposed electrode surface 38 and extra-pulposus        exposed electrode surface 42 (such as by configuring        intra-pulposus exposed electrode surface 38 to be a cathode, and        extra-pulposus exposed electrode surface 42 to be an anode), and    -   in the oxygen-generating mode of operation, generate oxygen        within nucleus pulposus 34 by electrolysis, by applying a mean        voltage of at least 1.23 V (e.g., between 1.23 V and 1.5 V, and        typically no more than 2V), between intra-pulposus exposed        electrode surface 38 and the extra-pulposus exposed electrode        surface (such as by configuring intra-pulposus exposed electrode        surface 38 to be an anode, and extra-pulposus exposed electrode        surface 42 to be a cathode).

For some of these applications, control circuitry 50 is activated to,during a period of time, assume (a) the electroosmotic mode of operationat least 10 times for an aggregate first duration and (b) theoxygen-generating mode of operation at least 10 times for an aggregatesecond duration that is less than 10% of the aggregate first duration,such as less than 1% of the aggregate first duration.

Reference is still made to FIGS. 1A-B and 2. For some applications,delivered cells 32 are supported by activating control circuitry 50 tointermittently drive, during a plurality of sessions, intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive the nutrient-containing fluid into nucleuspulposus 34.

For some of these applications:

-   -   an average duration of non-activation periods between sequential        ones of the sessions is at least 12 hours,    -   the plurality of sessions includes at least 10 sessions,    -   the plurality of sessions extends over at least one week, such        as over at least one month, and/or    -   at least one the plurality of sessions commences at least one        week (such as at least one month) after another one of the        plurality of sessions commences.

For some of these applications, delivered cells 32 are supported byactivating control circuitry 50 to intermittently drive intra-pulposusand extra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive the nutrient-containing fluid into nucleuspulposus 34 during one or more of the sessions (e.g., during exactly oneof the sessions) during each 24-hour period. For example, the one ormore of the sessions (e.g., the exactly one of the sessions) may be atnight, such as during sleep of the subject at night.

For some of these applications, delivered cells 32 are supported byactivating control circuitry 50 to drive intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive the nutrient-containing fluid into nucleuspulposus 34 based on a circadian cycle of the subject.

Reference is again made to FIGS. 1A-B, and is additionally made to FIG.3, which is a flowchart schematically illustrating a method for treatingintervertebral disc 20, in accordance with some applications of thepresent invention. The method of FIG. 3 may be practiced in combinationwith any of the techniques described hereinabove for the method of FIG.2, mutatis mutandis.

At a gene therapy administration step 130 of the method, gene therapy isadministered to nucleus pulposus cells of nucleus pulposus 34 ofintervertebral disc 20. For example, the therapeutic gene (e.g., insaline solution), or a biological construct encoding the therapeuticgene (e.g., in saline solution), may be delivered to nucleus pulposus34, such as described hereinabove with reference to FIG. 1A regardingcells 32 at cell delivery step 30 of the method of FIG. 2, mutatismutandis.

At an intra-pulposus electrode implantation step 136, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 140, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

For some applications, the gene therapy includes one or more of thefollowing types of gene therapy:

-   -   virus-mediated (e.g., using a retrovirus, an adenovirus, an        adeno-associated virus, a baculovirus, a lentivirus,    -   non-virus-mediated (e.g., microbubble-enhanced ultrasound,        polyplex micelle, RNA interference (siRNA)), or    -   CRISPR (e.g., Cas9).

For some applications, the gene therapy is implemented using techniquesdescribed in an article by Takeoka Y et al., entitled, “Gene TherapyApproach for Intervertebral Disc Degeneration: An Update,” Neurospine.2020 March; 17(1): 3-14, which is incorporated herein by reference.

At a gene support step 146, the gene therapy is supported by activatingcontrol circuitry 50 to drive intra-pulposus and extra-pulposus exposedelectrode surfaces 38 and 42 to electroosmotically drivenutrient-containing fluid into nucleus pulposus 34.

Reference is again made to FIGS. 1A-B, and is additionally made to FIG.4, which is a flowchart schematically illustrating a method for treatingintervertebral disc 20, in accordance with some applications of thepresent invention. The method of FIG. 4 may be practiced in combinationwith any of the techniques described hereinabove for the method of FIG.2, mutatis mutandis.

At a growth factor delivery step 230 of the method, a growth factor isdelivered to nucleus pulposus 34 of intervertebral disc 20. For example,the growth factor (e.g., in saline solution) may be injected intonucleus pulposus 34 and/or delivered to nucleus pulposus 34 in otherways, such as described hereinabove with reference to FIG. 1A regardingcells 32 at cell delivery step 30 of the method of FIG. 2, mutatismutandis. The growth factor may be delivered with or without viralvectors.

At an intra-pulposus electrode implantation step 236, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 240, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

For some applications, the growth factor includes a member of thetransforming growth factor-beta (P) superfamily, IGF-1, GDF-5, bonemorphogenetic protein (BMP)-2, BMP-7, rhDGF-5, rhGDF-5, anti-NGF (nervegrowth factor), or a platelet-derived growth factor. See, for example,Kennon J C et al., “Current insights on use of growth factors as therapyfor Intervertebral Disc Degeneration,” Biomol Concepts. 2018 May 19;9(1):43-52.

Optionally, the growth factor is delivered in a liposomal formation,which may provide slow drug delivery over a prolonged period of time.See, for example, Akbarzadeh A et al., “Liposome: classification,preparation, and applications,” Nanoscale Res Lett. 2013; 8(1): 102,published online 2013 Feb. 22.

At a growth factor support step 246, the growth factor is supported byactivating control circuitry 50 to drive intra-pulposus andextra-pulposus exposed electrode surfaces 38 and 42 toelectroosmotically drive nutrient-containing fluid into nucleus pulposus34.

Reference is again made to FIGS. 1A-B, and is additionally made to FIG.5, which is a flowchart schematically illustrating a method for treatingintervertebral disc 20, in accordance with some applications of thepresent invention. The method of FIG. 5 may be practiced in combinationwith any of the techniques described hereinabove for the method of FIG.2, mutatis mutandis.

At an intra-pulposus electrode implantation step 336, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 340, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

At an electroosmotic fluid driving step 356, control circuitry 50 isactivated to drive intra-pulposus and extra-pulposus exposed electrodesurfaces 38 and 42 to electroosmotically drive fluid into nucleuspulposus 34.

At an enzyme delivery step 358, an enzyme is delivered to intervertebraldisc 20 or tissue around intervertebral disc 20 so as to facilitateelectroosmotically driving the fluid into nucleus pulposus 34. Forexample, the enzyme (e.g., in saline solution) may be injected intonucleus pulposus 34 and/or delivered to nucleus pulposus 34 in otherways, such as described hereinabove with reference to FIG. 1A regardingcells 32 at cell delivery step 30 of the method of FIG. 2, mutatismutandis. In applications in which the enzyme is delivered tissue aroundintervertebral disc 20, some of the enzyme moves (e.g., flows) intonucleus pulposus 34, optionally because of the electroosmoticallydriving of fluid into nucleus pulposus 34 by activation of controlcircuitry 50 to drive intra-pulposus and extra-pulposus exposedelectrode surfaces 38 and 42, such as described herein.

For example, the enzyme therapy may improve the diffusion of the fluid(and, optionally, molecules in the fluid) into nucleus pulposus 34. Forsome applications, the enzyme therapy facilitates electroosmoticallydriving the fluid into nucleus pulposus 34 by decalcifying a vertebralendplate of disc 20 and/or by promoting the porosity of a vertebralendplate, both of which may facilitate inflow of fluid at a lesserresistance.

For some applications, the enzyme includes matrix metalloproteinase-8(MMP-8), bromelain, and/or papain.

Reference is again made to FIGS. 1A-B, and is additionally made to FIG.6, which is a flowchart schematically illustrating a method for treatingintervertebral disc 20, in accordance with some applications of thepresent invention. The method of FIG. 6 may be practiced in combinationwith any of the techniques described hereinabove for the method of FIG.2, mutatis mutandis. The method of FIG. 6 may also be practiced incombination with any of the other methods described herein.

At an intra-pulposus electrode implantation step 436, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 440, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

At an electroosmotic fluid driving step 456, control circuitry 50 isactivated to drive intra-pulposus and extra-pulposus exposed electrodesurfaces 38 and 42 to electroosmotically drive fluid from body 44 of thesubject into nucleus pulposus 34, such as to increase pressure inintervertebral disc 20. For example, techniques may be used that aredescribed in one or more of the patent application publications andpatents incorporated hereinbelow by reference.

At a supplemental fluid delivery step 460, supplemental fluid isdelivered (e.g., injected) to intervertebral disc 20 (nucleus pulposus34 or annulus fibrosus 48) or tissue surrounding intervertebral disc 20.For example, the supplemental fluid may improve electrical conductivityof disc tissue and provide initial flushing of any high cytokine levelsthat may occur.

For some applications, delivering (e.g., injecting) the supplementalfluid comprises delivering (e.g., injecting) saline solution tointervertebral disc 20 (nucleus pulposus 34 or annulus fibrosus 48) ortissue surrounding intervertebral disc 20.

For some applications, delivering (e.g., injecting) the supplementalfluid comprises delivering (e.g., injecting) a nutrient-containing fluidto intervertebral disc 20 (nucleus pulposus 34 or annulus fibrosus 48)or tissue surrounding intervertebral disc 20.

For some applications, the supplemental fluid is intermittently injectedinto intervertebral disc 20 (nucleus pulposus 34 or annulus fibrosus 48)or tissue surrounding intervertebral disc 20 during a plurality ofdelivery sessions, and control circuitry 50 is activated tointermittently drive, during a plurality of driving sessions,intra-pulposus and extra-pulposus exposed electrode surfaces 38 and 42to electroosmotically drive the supplemental fluid into nucleus pulposus34.

For some applications, at supplemental fluid delivery step 460, thesupplemental fluid is delivered from a reservoir implanted in body 44 ofthe subject. Reference is again made to FIGS. 1A-B, and is additionallymade to FIG. 7A, which is a flowchart schematically illustrating amethod for treating degeneration of intervertebral disc 20, inaccordance with some applications of the present invention.

The method of FIG. 7A may be practiced in combination with any of thetechniques described hereinabove for the method of FIG. 2, mutatismutandis. The method of FIG. 7A may also be practiced in combinationwith any of the other methods described herein.

At a biomaterial delivery step 530 of the method, a biomaterialconfigured to treat the degeneration is delivered (e.g., injected) tointervertebral disc 20 (nucleus pulposus 34 or annulus fibrosus 48) ortissue around intervertebral disc 20.

At an intra-pulposus electrode implantation step 536, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 540, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

At an electroosmotic fluid driving step 556, control circuitry 50 isactivated to drive intra-pulposus and extra-pulposus exposed electrodesurfaces 38 and 42 to electroosmotically drive fluid into nucleuspulposus 34. The biomaterial in intervertebral disc 20 (e.g., nucleuspulposus 34) may enhance the electroosmotic driving of the fluid intonucleus pulposus 34. Typically, the fluid includes nutrient, such as thenutrients described hereinabove with reference to FIGS. 1A-B and 2.

For some applications, the biomaterial includes:

-   -   a gel, e.g., a cell-derived matrix gel or a hydrogel,    -   a structural filler,    -   a matrix, e.g., an extracellular matrix (ECM),    -   a polymer, e.g., a protein-based polymer or a synthetic polymer,        or    -   hyaluronic acid.

Injection of hyaluronic acid into the disc has been shown to slow discdegeneration; see, for example, Omlor G W et al., “Injection of apolymerized hyaluronic acid/collagen hydrogel matrix in an in vivoporcine disc degeneration model,” Eur Spine J 2012 September;21(9):1700-8, Epub 2012 Apr. 25.

Reference is again made to FIGS. 1A-B, and is additionally made to FIG.7B, which is a flowchart schematically illustrating a method fortreating degeneration of intervertebral disc 20, in accordance with someapplications of the present invention.

The method of FIG. 7B may be practiced in combination with any of thetechniques described hereinabove for the method of FIG. 2, mutatismutandis. The method of FIG. 7B may also be practiced in combinationwith any of the other methods described herein.

At an anti-inflammatory agent delivery step 630 of the method, ananti-inflammatory agent is delivered (e.g., injected) to intervertebraldisc 20 (nucleus pulposus 34 or annulus fibrosus 48) or tissue aroundintervertebral disc 20, in order to treat the degeneration, such as byslowing or halting the degenerative process.

At an intra-pulposus electrode implantation step 636, at least oneintra-pulposus exposed electrode surface 38 is implanted (typicallychronically) in nucleus pulposus 34, such as shown in FIG. 1B.

At an extra-pulposus electrode implantation step 640, at least oneextra-pulposus exposed electrode surface 42 is implanted (typicallychronically) in body 44 of the subject outside nucleus pulposus 34, asshown in FIG. 1B. For example, extra-pulposus exposed electrode surface42 may be implanted in a vicinity of an external surface of annulusfibrosus 48 of disc 20, either in physical contact with the externalsurface or not in physical contact with the external surface.

Alternatively, the at least one extra-pulposus exposed electrode surface42 is placed outside body 44 of the subject, such as on an externalsurface of the skin (configuration not shown).

At an electroosmotic fluid driving step 656, control circuitry 50 isactivated to drive intra-pulposus and extra-pulposus exposed electrodesurfaces 38 and 42 to electroosmotically drive fluid into nucleuspulposus 34.

For some applications, the anti-inflammatory agent includes:

-   -   platelet rich plasma (PRP),    -   curcumin,    -   an IL-6 receptor antagonist,    -   methylene blue,    -   TGF-B1 binding polypeptide, e.g., YH14618 7 peptide amino        (Yuhan),    -   rhTGFbl, rhCTGF (Notogen),    -   NFkB (AnGes),    -   A2M (Alpha-2-macroglobulin), or    -   anti-TNF-alph.

Injection of hyaluronic acid into the disc has been shown to slow discdegeneration; see, for example, Omlor G W et al., “Injection of apolymerized hyaluronic acid/collagen hydrogel matrix in an in vivoporcine disc degeneration model,” Eur Spine J 2012 September;21(9):1700-8, Epub 2012 Apr. 25.

Reference is now made to FIGS. 1A-7B. For some applications, thetechniques described herein are combined with activating controlcircuitry 50 to drive intra-pulposus and extra-pulposus exposedelectrode surfaces 38 and 42 to electroosmotically drive fluid from body44 of the subject into nucleus pulposus 34, such as to increase pressurein nucleus pulposus 34. For example, techniques may be used that aredescribed in one or more of the patent application publications andpatents incorporated hereinbelow by reference. The increase in fluid innucleus pulposus 34 generally treats or prevents further degeneration ofthe disc caused at least in part by loss of fluid.

For some applications, control circuitry 50 is activated to:

-   -   repeatedly assume a pressure-increasing mode of operation in        alternation with a support mode of operation,    -   in the pressure-increasing mode of operation, drive        intra-pulposus and extra-pulposus exposed electrode surfaces 38        and 42 to electroosmotically drive fluid from body 44 of the        subject into nucleus pulposus 34, such as to increase pressure        in nucleus pulposus 34, and    -   in the support mode of operation, support the delivered cells,        the gene therapy, or the growth factor, as described        hereinabove.

For some applications, a housing containing control circuitry 50 isinjectable, with an anchor at the proximal end. One or moreextra-pulposus exposed electrode surfaces 42 are fixed to an externalsurface of the housing. For example, the housing may be implantedimmediately posterior to the spinal column. For some applications,control circuitry 50 is configured to be implanted subcutaneously, ifthe housing containing the control circuitry is small. Alternatively,for some applications, control circuitry 50 is configured to beimplanted or elsewhere in the subject's body, if the housing of thecontrol circuitry is larger (e.g., includes batteries).

For some applications, control circuitry 50 is driven by an externalcontroller that is in wireless or wired communication with controlcircuitry 50. For some applications, the external controller is mountedon a bed of the subject (e.g., disposed within a mattress), and isconfigured to activate control circuitry 50 only at night, and/or onlywhen the subject is sleeping.

For some applications, any of the techniques described herein arecombined with injection of a narcotic, such as liposomal bupivacaine ormethylene blue, into the disc, to reduce pain; see, for example, Peng Bet al., “A randomized placebo-controlled trial of intradiscal methyleneblue injection for the treatment of chronic discogenic low back pain,”Pain 2010 April; 149(1):124-9.

Reference is made to FIGS. 8 and 9A-J, which are schematic illustrationsof a kit 190 and a method for implanting an electrode 200 in nucleuspulposus 34, in accordance with an application of the present invention.Kit 190 comprises electrode 200, a needle 202, and a stylet 206.Electrode 200 (such as distal non-electrically-insulated longitudinalsegment 208, described immediately below) may comprise the at least oneintra-pulposus exposed electrode surface 38 described hereinabove withreference to FIGS. 1A-7B.

For some applications, electrode 200 comprises coiled wire 204 and atubular insulator 218 in which coiled wire 204 is partially disposed,with a distal non-electrically-insulated longitudinal segment 208 ofcoiled wire 204 extending distally out of a distal end of tubularinsulator 218, and, typically, a proximal non-electrically-insulatedlongitudinal segment 210 of coiled wire 204 extending proximally out ofa proximal end of tubular insulator 218.

As shown in FIG. 9A, needle 202 is inserted into tissue of a body of asubject and is distally advanced through the tissue into nucleuspulposus 34 of intervertebral disc 20 of the subject, such that (a) adistal longitudinal portion of needle 202, including a distal end of theneedle, is positioned within nucleus pulposus 34, and (b) a proximalportion of needle 202, including a proximal end 212 of the needle,remain outside the subject's body.

As shown in FIG. 9B, electrode 200 is advanced distally into needle 202while a stylet 206 is disposed within a longitudinal channel defined bycoiled wire 204. Also as shown in FIG. 9B, electrode 200 and stylet 206are together distally advanced through needle 202 until distalnon-electrically-insulated longitudinal segment 208 of coiled wire 204of electrode 200 and a distal portion of stylet 206, including thedistal end of stylet 206, is positioned within nucleus pulposus 34.Stylet 206, needle 202, and coiled wire 204 remain partially outside thesubject's body, with stylet 206 and coiled wire 204 extending proximallyout of proximal end 212 of needle 202.

Stylet 206 generally reinforces and stiffens coiled wire 204, in orderto enable coiled wire 204 to better withstand bending forces duringdelivery, despite the low natural pushability of coiled wire 204 becauseof its high flexibility, and the radial gap between coiled wire 204 andthe inner surface of needle 202. Stylet 206 also aids with handlingelectrode 200 prior to injection, by protecting the electrode fromunintentional bending that might damage the electrode.

For some applications, stylet 206 comprises a cobalt chrome material orstainless steel, which optionally is thermally treated in order toharden the material while remain sufficiently flexible. These materialsmay enable good pushability even in configuration in which the stylet isvery narrow, such as a 0.008″ diameter. Alternatively or additionally,stylet 206 may can undergo an electropolishing process to reducefriction.

As shown in FIGS. 9C-G, thereafter, while stylet 206 is held axiallystationary with respect to nucleus pulposus 34, needle 202 is proximallywithdrawn from the subject's body, leaving distalnon-electrically-insulated longitudinal segment 208 of coiled wire 204within nucleus pulposus 34, with a distal end 216 of stylet 206 withinthe longitudinal channel of coiled wire 204, including within distalnon-electrically-insulated longitudinal segment 208.

Because stylet 206 serves as an internal support for electrode 200,which is typically highly flexible, stylet 206 serves as a supportivestructure for fine-tuning placement of electrode 200 after needle 202has been withdrawn, in addition to aiding with pushing the electrodedistally during exchange with needle 202.

As shown in FIG. 9H, stylet 206 is proximally withdrawn from thesubject's body and from the longitudinal channel of coiled wire 204,while leaving distal non-electrically-insulated longitudinal segment 208of coiled wire 204 within nucleus pulposus 34, as shown in FIGS. 9I-J.

For some applications, distally advancing needle 202 through the tissueinto nucleus pulposus 34 as shown in FIG. 9A, comprises distallyadvancing needle 202 through the tissue into nucleus pulposus 34 whiledistal non-electrically-insulated longitudinal segment 208 of coiledwire 204 is constrained only by needle 202 and stylet 206.

For some applications in which electrode 200 comprises tubular insulator218, proximally withdrawing needle 202, as shown in FIGS. 9C-G,comprises proximally withdrawing needle 202 while leaving (a) distalnon-electrically-insulated longitudinal segment 208 of coiled wire 204within nucleus pulposus 34, and (b) tubular insulator 218 at leastpartially within the subject's body, at least partially outside nucleuspulposus 34. Optionally, a distal portion of tubular insulator 218 isleft at least partially disposed within annulus fibrosus 48.

For some applications, coiled wire 204 of electrode 200 is coated with afriction-reducing coating (e.g., PTFE or ePTFE), such as to reducefriction during proximal withdrawal of stylet 206. Alternatively oradditionally, coiled wire 204 of electrode 200 is coated with a medicalgrade material, such as a thin layer of silicone or PEBA.

For some applications, needle 202 includes a plurality of radiopaquemarkers, and distally advancing needle 202 through the tissue intonucleus pulposus 34, as shown in FIG. 9A, comprises observing theradiopaque markers to confirm that the distal longitudinal portion ofneedle 202 is disposed in nucleus pulposus 34. For example, theplurality of radiopaque markers may be arranged as a ruler along needle202. Alternatively or additionally, the radiopacity of stylet 206 and/ordistal-most non-coiled tip 214, described hereinabove, and/or optionalradiopaque markers coupled to stylet 206 may help the physician assessthe length of the portion of electrode 200 that is to be injected(because electrode 200 itself is typically not particularly radiopaque).

For some applications, electrode 200 includes a distal-most non-coiledtip 224, which is disposed at a distal end of coiled wire 204, and whichis shaped so as to define a proximally-facing surface. For some of theseapplications, distal-most non-coiled tip 214 is shaped so as to definean atraumatic distally-facing end surface, which increases theelectrical contract surface area. For some applications, the atraumaticdistally-facing end surface is spherical (as shown) or semi-spherical(configuration not shown). For some applications, distal-most non-coiledtip 224 is electrically conductive and is coupled in electricalcommunication with coiled wire 204. In addition, distal-most non-coiledtip 214 may serve to prevent stylet 206 from exiting the distal end ofcoiled wire 204, and/or to allow the physician to push electrode 200forward from the electrode's distal end by pushing stylet 206 againstdistal-most non-coiled tip 214 from within coiled wire 204. Optionally,distal-most non-coiled tip 214 comprises a metal, such as titanium, suchas a radiopaque metal.

Reference is again made to FIG. 8. For some applications, coiled wire204 is shaped so as to define an intra-annular longitudinal segment 226that has a greater pitch than respective pitches of portions of coiledwire 204 immediately proximal and distal to intra-annular longitudinalsegment 226. For example, the pitch of intra-annular longitudinalsegment 226 may be at least 2 times, such as least 4 times, therespective pitches of the portions of coiled wire 204 immediatelyproximal and distal to intra-annular longitudinal segment 226, and/orthe pitch of intra-annular longitudinal segment 226 may be between 0.5and 1.5 mm, such as between 0.75 and 1.25 mm, e.g., 1 mm. Typically,intra-annular longitudinal segment 226 has a length of between 0.8 and 1mm. Typically, intra-annular longitudinal segment 226 is disposed withintubular insulator 218.

For example, the pitch of distal non-electrically-insulated longitudinalsegment 208 may be between 0.1 and 0.15 mm.

For example, the pitch of the portion of coiled wire 204 proximal tointra-annular longitudinal segment 226 may be between 0.2 and 0.3 mm.

The respective pitches of distal non-electrically-insulated longitudinalsegment 208 and the portion of coiled wire 204 proximal to intra-annularlongitudinal segment 226 may be the same as or different from eachother.

Reference is again made to FIG. 9J. Typically, annulus fibrosus 48squeezes the longitudinal portion of electrode 200 disposed withinannulus fibrosus 48. Tissue of the annulus fibrosus generally protrudesbetween turns of coiled wire 204, typically by pressing, between turnsof coiled wire 204, the thin wall of a portion of tubular insulator 218that surrounds the longitudinal portion of electrode 200 disposed withinannulus fibrosus 48, thereby:

-   -   creating a good seal between the annulus fibrosus and the        electrode, thereby inhibiting flow of liquid and/or biological        matter in and out of the nucleus pulposus, and/or    -   anchoring (fixing) the electrode to the annulus fibrosus and        disc, such that a separate fixation element (such as a suture or        clip) is typically not required to hold the electrode in place        with respect to the annulus fibrosus or disc.

Tubular insulator 218 typically comprises a material that is configuredto remain intact, such as for long-term delivery of fluid.

For some applications, the thin wall of the portion of tubular insulator218 that surrounds the longitudinal portion of electrode 200 disposedwithin annulus fibrosus 48 has a thickness of between 0.02 and 0.07 mm(between 0.001″ and 0.003″).

Reference is still made to FIG. 9J. For some applications, uponimplantation of electrode 200, intra-annular longitudinal segment 226 isat least partially disposed within annulus fibrosus 48, typicallysurrounded by a distal portion of tubular insulator 218. The greaterpitch of intra-annular longitudinal segment 226 generally reduces theradial strength of coiled wire 204, thereby allowing annulus fibrosus 48to naturally squeeze the coiled portion more tightly, thereby improvingsealing and/or anchoring between the electrode and the annulus fibrosusupon removal of stylet 206.

Reference is now made to FIG. 10, which is a schematic illustration of aconnector 300, in accordance with an application of the presentinvention. Connector 300 is typically configured to be couplable to aproximal portion of electrode 200, or another type of electrode, uponcompletion of implantation of the electrode. Connector 300 provides:

-   -   a fluid flow path between an external fluid container 302 and a        channel defined by tubular insulator 218 between connector 300        and a distal end of tubular insulator 218 disposed within        nucleus pulposus 34, and    -   an electrical connection 304 between coiled wire 204 and control        circuitry 306.

Connector 300 is shaped so as to define:

-   -   a fluid port 308, for example through a lateral wall of        connector 300, for connection to fluid container 302, and    -   an electrode connector port 309, which is configured to provide        a liquid-tight seal with tubular insulator 218.

The fluid flow path may be either one-way or two-way.

For example, connector 300 may comprise a conductive screw 310 that isconfigured to make electrical connection 304.

Optionally, connector 300 comprises a seal 312 to prevent fluidcommunication between the channel of tubular insulator 218 andconnection 304.

For some applications, connector 300 is used to deliver any of thefluids, cells, or other materials described hereinabove to nucleuspulposus 34. Connector 300 may be used temporarily soon afterimplantation of the electrode, and then decoupled from the electrode, ormay be permanently attached to the electrode, and thus may beimplantable in the body of the subject, as may be fluid container 302(e.g., with a self-sealing subcutaneous port for refilling).

Optionally, if the channel within tubular insulator 218 should becomeblocked over time (such as by fluids, blood, or tissue), a flexiblestylet is inserted into channel to clear the channel before delivery ofliquid or other materials through the channel.

In some applications of the present invention, the techniques andapparatus described herein are combined with techniques and apparatusdescribed in one or more of the following applications, which areassigned to the assignee of the present application and are incorporatedherein by reference:

-   U.S. Pat. No. 8,577,469 to Gross;-   U.S. Pat. No. 9,731,122 to Gross;-   U.S. Pat. No. 9,770,591 to Gross et al.;-   U.S. Pat. No. 9,950,156 to Gross et al.;-   U.S. Pat. No. 10,518,085 to Gross et al.; and/or-   US Patent Application Publication 2021/0059830 to Gross.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1-27. (canceled)
 28. A method for treating an intervertebral disc of asubject, the method comprising: delivering a growth factor to a nucleuspulposus of the intervertebral disc; implanting at least oneintra-pulposus exposed electrode surface in the nucleus pulposus;implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; and supporting thegrowth factor by activating control circuitry to drive theintra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive nutrient-containing fluid into the nucleuspulposus.
 29. The method according to claim 28, wherein delivering thegrowth factor to the nucleus pulposus comprises injecting the growthfactor into the nucleus pulposus through a hollow needle.
 30. The methodaccording to claim 28, wherein delivering the growth factor to thenucleus pulposus comprises delivering the growth factor to the body ofthe subject outside the nucleus pulposus such that the growth factormoves into the nucleus pulposus.
 31. The method according to claim 30,wherein delivering the growth factor to the body of the subject outsidethe nucleus pulposus comprises delivering the growth factor to avertebral endplate such that the growth factor moves into the nucleuspulposus.
 32. The method according to claim 30, wherein delivering thegrowth factor to the body of the subject outside the nucleus pulposuscomprises delivering the growth factor to an annulus fibrosus of theintervertebral disc such that the growth factor moves into the nucleuspulposus.
 33. The method according to claim 30, wherein delivering thegrowth factor to the nucleus pulposus comprises, while at least some ofthe growth factor is outside the nucleus pulposus, activating thecontrol circuitry to drive the intra-pulposus and the extra-pulposusexposed electrode surfaces to electroosmotically drive the growth factorinto the nucleus pulposus.
 34. The method according to claim 28, whereinsupporting the growth factor comprises supporting the growth factor byactivating the control circuitry to apply, between the intra-pulposusexposed electrode surface and the extra-pulposus exposed electrodesurface, a mean voltage insufficient to cause electrolysis.
 35. Themethod according to claim 28, wherein the nutrient-containing fluidincludes oxygen, and wherein supporting the growth factor comprisessupporting the growth factor by activating the control circuitry todrive the intra-pulposus and the extra-pulposus exposed electrodesurfaces to electroosmotically drive the oxygen-containing fluid intothe nucleus pulposus.
 36. The method according to claim 28, wherein thenutrient-containing fluid includes glucose, and wherein supporting thegrowth factor comprises supporting the growth factor by activating thecontrol circuitry to drive the intra-pulposus and the extra-pulposusexposed electrode surfaces to electroosmotically drive theglucose-containing fluid into the nucleus pulposus.
 37. The methodaccording to claim 28, wherein supporting the growth factor comprisessupporting the growth factor by activating the control circuitry tointermittently drive, during a plurality of sessions, the intra-pulposusand the extra-pulposus exposed electrode surfaces to electroosmoticallydrive the nutrient-containing fluid into the nucleus pulposus.
 38. Themethod according to claim 37, wherein an average duration ofnon-activation periods between sequential ones of the sessions is atleast 12 hours.
 39. The method according to claim 37, wherein theplurality of sessions includes at least 10 sessions.
 40. The methodaccording to claim 37, wherein supporting the growth factor comprisessupporting the growth factor by activating the control circuitry tointermittently drive the intra-pulposus and the extra-pulposus exposedelectrode surfaces to electroosmotically drive the nutrient-containingfluid into the nucleus pulposus during one or more of the sessionsduring each 24-hour period.
 41. The method according to claim 40,wherein supporting the growth factor comprises supporting the growthfactor by activating the control circuitry to intermittently drive theintra-pulposus and the extra-pulposus exposed electrode surfaces toelectroosmotically drive the nutrient-containing fluid into the nucleuspulposus during exactly one of the sessions during each 24-hour period.42. The method according to claim 37, wherein the plurality of sessionsextends over at least one week.
 43. The method according to claim 28,wherein supporting the growth factor comprises supporting the growthfactor by activating the control circuitry to apply direct currentbetween the intra-pulposus and the extra-pulposus exposed electrodesurfaces.
 44. A method for treating an intervertebral disc of a subject,the method comprising: implanting at least one intra-pulposus exposedelectrode surface in a nucleus pulposus of the intervertebral disc;implanting at least one extra-pulposus exposed electrode surface in abody of the subject outside the nucleus pulposus; delivering a growthfactor to the body of the subject outside the nucleus pulposus; andwhile at least some of the growth factor is outside the nucleuspulposus, activating control circuitry to drive the intra-pulposus andthe extra-pulposus exposed electrode surfaces to electroosmoticallydrive the growth factor into the nucleus pulposus.
 45. The methodaccording to claim 44, further comprising supporting the growth factorby activating control circuitry to drive the intra-pulposus and theextra-pulposus exposed electrode surfaces to electroosmotically drivenutrient-containing fluid into the nucleus pulposus.
 46. The methodaccording to claim 44, wherein delivering the growth factor to the bodyof the subject outside the nucleus pulposus comprises delivering thegrowth factor to a vertebral endplate.
 47. The method according to claim44, wherein delivering the growth factor to the body of the subjectoutside the nucleus pulposus comprises delivering the growth factor toan annulus fibrosus of the intervertebral disc.